The trans-fused γ-lactones, epianastrephin (1) and anastrephin (2) (Scheme 1), are male-produced sex and aggregation pheromones of Caribbean (Anastrepha suspensa), Mexican (Anastrepha ludens), and South American (Anastrepha fraterculus) fruit flies (Nation, J. L., Ann. Entomol. Soc. Amer., 65: 1364 (1972); Nation, J. L., Environ. Entomol., 4: 27 (1975); Lima, I. S., et al., J. Braz. Chem. Soc., 12: 196 (2001)). In most agriculturally important regions of the United States, outbreaks of A. suspensa and A. ludens are regulated with quarantines to minimize potential damage of commercially valuable host fruit (USDA, APHIS, Fruit Fly Exclusion and Detection Programs 2011, Exotic Fruit Fly Strategic Plan FY2011-2015). Currently, trapping and monitoring devices rely on food-based lures, while a lure involving the epianastrephin (1) and anastrephin (2) pheromones is lacking because of insufficient synthetic routes to the quantities required for commercial-scale utilization (Tan, K. H., et al., Pheromones, male lures, and trapping of tephritid fruit flies; and Epsky, N. D., et al., History and development of food-based attractants, IN: Trapping and the detection, control, and regulation of tephritid fruit flies, Shelly, T., et al., Eds., Springer: Dordrecht, 2014, pp. 15-118).

Pheromones 1 and 2 are naturally emitted from the oral secretions deposited by males to mark mating sites, and the mechanism of release provides insight toward their potential agricultural use as well as the importance of an efficient synthetic route toward this end. In addition to 1 and 2, oral secretions of males contain trans-fused γ-hydroxy acids 5a (hydrolysate 1→5a) and 5b (hydrolysate 2→5b), dehydration product 7 (derived from 5a or 5b), and glucoconjugate 8. All of these compounds are related through aqueous equilibrium that serves to abiotically release the relatively volatile lactones 1 and 2 over extended periods of time (Lu, F., and Teal, P. E. A., Arch. Insect Biochem. Physiol., 48: 144 (2001); Walse, S. S., et al., Green Chem. Lett. Rev., 1: 205 (2008); Walse, S. S., et al., U.S. Pat. No. 8,128,948, Compositions and Methods for Attracting Anastrepha Species, (June 2008)). Thus, an efficient synthesis of compounds 1 and 2 provides access to pheromone (1 and 2) as well as precursory forms 5a, 5b, 7, or 8 (or combinations thereof), all useful for the attraction of certain Anastrepha species (Scheme 2).

Several racemic and enantioselective syntheses of pheromones 1 and 2 are known (see, Battiste, M. A., et al., Tetrahedron Lett., 24: 2611 (1983); and references cited therein; for additional syntheses of anastrephin and epianastephin, see: Visnick, M., Ph.D. Dissertation, University of Florida, 1983; Strekowski, L., et al., J. Org. Chem., 51: 4836 (1986); Saito, A., et al., Chem. Lett. 729 (1984); for a synthesis of mixtures of 1 and 2 via an acid-catalyzed rearrangement of suspensolide (6), see: Battiste, M. A., et al., Tetrahedron Lett., 32: 5303 (1991); for biomimetic synthesis via suspensolide, see: Mori, K., et al., Ann. Chem., 167 (1988); Battiste, M. A., et al., Tetrahedron Lett., 29: 6565 (1988); Vecchio, G. H.-D., and Oehlschlager, A. C., J. Org. Chem., 59: 4853 (1994); Battiste, M. A., et al., J. Org. Chem., 61: 6454 (1996); for enantioselective syntheses of (−)-anastrephin, (−)-epianastrephin and (+)-epianastrephin, see: Wada, K., et al., Synlett., 27: A-E (2016); Tadano, K., et al., Tetrahedron Lett., 33: 7899 (1992); Tadano, K., et al., J. Org. Chem., 58: 6266 (1993); Irie, O., and Shishido, K., Chem. Lett., 53 (1995); Schultz, A. G., and Kirincich S. J., J. Org. Chem., 61: 5626 (1996); for access to trans-lactones via cyclization of the corresponding trans-fused γ-hydroxy acids 5a (condensation 5a→1) and 5b (condensation 5b→2), see: Strekowski, L., and Battiste, M. A., Tetrahedron Lett., 22: 279 (1981)). However, none of the aforementioned synthetic routes have satisfied the mass production requirements for formulation studies, field trials and commercialization (Nation, J. L., The role of pheromones in the mating system of Anastrepha fruit flies, IN: Fruit flies: their biology, natural enemies and control, Robinson A. S., and Hopper, G., Eds., Elsevier: Amsterdam, 1989, Vol. 3A, pp 189-205). A short and scalable process for the diastereoselective synthesis of compounds of formula (±)-1 and (±)-2, therefore, would be highly desirable (note that A. suspensa produces a nearly racemic mixture of both 1 and 2 (ee range 55±3 (−)/45±3 (+) with the 3aS,7aS-configuration assigned to the major (−) enantiomers), see Strekowski, L., et al., J. Org. Chem., 51: 4836 (1986); Saito, A., et al., Chem. Lett., 729 (1984); Battiste, M. A., et al., Tetrahedron Lett., 32: 5303 (1991); for the reported biological activity of enantiomers of 1 and 2, see: Robacker, D. C., and Hart, W. G., Entomol. Exp. Appl., 39: 103 (1985); Robacker, D. C., et al., Entomol. Exp. Appl., 40: 123 (1986)).
Under acidic conditions, trans-fused γ-lactones of Formula (IV) would not be expected from compounds of Formula (II) (where R4 is H or R4 is C1-4 alkyl) (Scheme 3), as cis-fused γ-lactones formed with such catalysts as H2SO4 (Matsumoto, T., et al., Bull. Chem. Soc. Jpn., 45: 1147 (1972); Dobrev, A., and Ivanov, C., Synthesis, 8: 562 (1977); Watanabe, S., et al., J. Jpn. Oil Chem. Soc., 29: 43 (1980); Fujitga, T., et al., J. Org. Chem., 49: 1975 (1984)), amberlyst-15 resin (Bunce, R. A., et al., Synthetic Communications, 19: 2423 (1989)), and 12 (Fujita, T., et al., Synthesis, 12: 1846 (2001); Kasashima, Y., et al., J. Oleo Sci., 56: 189 (2007)). Further complicating these synthetic approaches, the acid-catalyzed isomerization of trans-fused γ-lactones of Formula (IV) to the thermodynamically more stable cis-fused γ-lactones readily occurs (Siato, A., et al., Chem. Lett., 1065 (1978); Hoye, T. R., and Kurth, M. J., J. Org. Chem., 43: 3693 (1978); Imamura, P. M., and Santiago, G. M. P., Synthetic Communications, 27: 2479 (1997)).
Similarly, under acid-conditions, we have observed the favored formation of cis-fused γ-lactones relative to trans-fused and the isomerization of the trans-fused γ-lactones to cis-fused. β-hydroxy ester of Formula (II) (where R1 is ethenyl, R2 is methyl, R3 is methyl, and R4 is t-butyl) was treated with catalytic I2 at 80° C. for 4 h in CH3CN to yield hydrolysis of the t-butyl ester and cyclization to afford a 10:3:1 mixture, respectively, of cis- and trans-fused γ-lactones 3, 1 and 4 as determined by 1H NMR (see, for the iodine-mediated hydrolysis of t-butyl esters, Yadav J. S., et al., Tetrahedron Lett., 47: 4921 (2006)) and lactonization (Fujita, T., et al., Synthesis, 1846 (2001)). Moreover, trans-fused γ-lactones 1 and 2 each isomerized to cis-fused γ-lactones 3 and 4 after treatment with BF3.Et2O in acetonitrile at room temperature for 24 h. Treatment of trans-fused γ-lactone 1 with 1 N aqueous HCl at 80° C. for 3 h gave predominately cis-fused γ-lactone 3 and trace amounts (<5%) of γ-lactone 4.
Consequently, the prior-art references as well as our preliminary experimentation teach away from our invention and indicate that the use of acidic conditions to form trans-fused γ-lactones of Formula (IV), in large excess relative to cis-fused analogs, from intermediates of Formula (II) (where R1, R2, R3, and R4 have the meanings of, for example, n, R1, R2, R3 and R4 in the Summary of the Invention section) would be high risk, non-obvious, and surprising.